Acute myeloid leukemia (AML) afflicts 13,000 new patients in the U.S. each year. About 9,000 people in this country died of this disease in 2007. A thorough understanding of the signaling pathways required for AML formation is necessary in order to develop much needed therapeutic treatments for AML patients. Therefore, there is a need to identify novel mutations and signaling pathways that contribute to AML. The long-term objective of these studies is to identify new mutations and signaling pathways that play critical roles in leukemogenesis. The specific objectives of these studies are to characterize the transforming properties of the receptor for interleukin-27 (IL27R), a type I cytokine receptor, and to determine the contribution of IL27R to the development of leukemia. This is very exciting because IL27R has never been linked to cancer and type I cytokine receptors have recently been shown to play important roles in various myeloid cell disorders. This suggests these cytokine receptors may play unappreciated roles in myeloid diseases including AML. The hypothesis for this work is that aberrant IL27R signaling is transforming and can contribute to leukemia development. This is based on our identification of IL27R in a novel functional genetic screen of transforming genes in AML. The transforming properties of IL27R will be evaluated through studies proposed in four specific aims. Specific aim 1 will focus on determining the mechanism by which IL27R initiates aberrant signal transduction. This will be done in myeloid cells by performing functional analyses on IL27R mutants to determine which regions of IL27R are responsible for transformation. Studies in this aim will also determine if IL27R dimerization plays a role in its transforming properties. Studies in specific aim 2 will determine which JAK and STAT signaling pathways are utilized by IL27R to transform myeloid cells. Studies in specific aim 3 will determine the transforming properties of IL27R in mice. These studies will utilize mouse models for leukemia to study IL27R-mediated leukemogenesis. Finally, studies in specific aim 4 will determine the extent to which IL27R contributes to human leukemia. These studies will include analyzing IL27R expression and function in AML cells from patients. The proposed studies are the first to investigate the novel transforming properties of IL27R, which we recently discovered, and will investigate potential novel therapeutic targets for AML.